Abnormal levels of glucose in the blood of humans can have a number of consequences. For example, fluctuations of blood glucose levels outside of the physiological range can result in one of two states, hypoglycemia and hyperglycemia. Hypoglycemia is defined as plasma glucose levels below normal (70 mg/dL). Hypoglycemia can be symptomatic or asymptomatic. For example, subjects suffering from postprandial hypoglycemia generally have symptoms of adrenergic stimulation including diaphoresis, anxiety, irritability, palpitations, tremor, and hunger. Such symptoms typically occur from about 2 to 4 hours postprandially and tend to occur suddenly with symptoms generally subsiding in about 15 to 20 minutes. Postprandial hypoglycemia is often idiopathic, however, it can be caused by early diabetes, alcohol intake, renal failure, and drug treatments.
In addition, a category of hypoglycemia exists which is designated as fasting hypoglycemia. Clinically, this form of hypoglycemia may have symptoms of neuroglycopenia including headache, fatigue, and mental dullness. In more severe cases, hypoglycemia can progress to confusion, blurring of vision, seizure, and ultimately loss of consciousness or seizure. Fasting hypoglycemia can occur with a fast of greater than 4 hours, and further can be caused by an insulinoma (insulin producing tumor) or resulting from self-administered insulin or intake of other hypoglycemic agents, alcohol abuse, liver disease (e.g., decreased gluconeogenesis), pituitary insufficiency, or adrenal insufficiency.
Hyperglycemia, on the other hand, refers to excessive levels of blood glucose in a subject. There are many forms of hyperglycemia, the primary form being diabetes, which is defined as hyperglycemia secondary to decreased insulin production or an increase in peripheral tissue resistance to the action of insulin. Insulin, in simple terms, is the hormone that unlocks the cells of the body, allowing glucose to enter those cells and feed them. In diabetic subjects, glucose cannot enter the cells and subsequently, glucose builds up in the blood and the body's cells literally starve to death. Although the cause of diabetes is not completely understood, genetics, environmental factors, and viral causes have been partially identified.
The American Diabetes Association reports that nearly 6% of the population in the United States, a group of 16 million people, has diabetes. The Association further reports that diabetes is the seventh leading cause of death in the United States, contributing to nearly 200,000 deaths per year. Diabetes is a chronic disease having no cure.
There are two major types of diabetes: Type I and Type II. Type I diabetes (formerly known as juvenile onset diabetes) is an autoimmune disease in which the body does not produce any insulin and most often occurs in young adults and children. People with Type I diabetes must take daily insulin injections to stay alive.
Type II diabetes is a metabolic disorder resulting from the body's inability to make enough, or properly to use, insulin. Type II diabetes accounts for 90-95% of diabetes. In the United States, Type II diabetes is nearing epidemic proportions, principally due to an increased number of older Americans and a greater prevalence of obesity and a sedentary lifestyle.
Diabetics having Type I diabetes typically are required to self-administer insulin using, e.g., a syringe or a pen with needle and cartridge. Continuous subcutaneous insulin infusion via implanted pumps is also available. Insulin itself was formally obtained from pork pancreas but is now made chemically identical to human insulin by recombinant DNA technology or by chemical modification of pork insulin. Although there are a variety of different insulins for rapid-, short-, intermediate-, and long-acting forms that may be used variously, separately or mixed in the same syringe, use of insulin for treatment of diabetes is not to be ignored.
The general characteristics of the symptoms of diabetes include the following: polyuria (high urine volume); hyperglycemia (high blood glucose levels); glucosuria (loss of glucose in urine); polydipsia (excessive thirst); polyphagia (excessive hunger); and sudden weight loss.
It has been observed that complications resulting from diabetes are the third leading cause of death in most developed countries. Diabetes is a risk factor for a variety of conditions including coronary heart disease, cerebrovascular stroke, neuropathy (nerve damage), nephropathy (kidney damage), retinopathy (eye damage), hyperlipidemia (excessive blood lipids), angiopathy (damage to blood vessels) and infection. For example, diabetes is said to be the leading cause of new cases of blindness in individuals in the range of ages between 20 and 74; from 12,000-24,00 people per year lose their sight because of diabetes. Diabetes is the leading cause of end-stage renal disease, accounting for nearly 40% of new cases. Nearly 60-70% of people with diabetes have mild to severe forms of diabetic nerve damage which, in severe forms, can lead to lower limb amputations. People with diabetes are 2-4 times more likely to have heart disease and to suffer strokes.
The healthcare costs associated with the treatment of diabetes and diabetic complications are enormous and projected to increase with the number of American living to older ages and the increased incidence of obesity. Much of the morbidity and mortality can be ameliorated by the use of insulin or oral medications (and in many cases weight loss), but the key to diabetes control is frequent measurement of blood glucose concentration. This is vital in determining the amount of insulin or oral medications that must be given.
Thus, it is highly recommended by the medical profession that subjects who are at risk or have been diagnosed with hypoglycemia, hyperglycemia (including diabetes), and/or glucose fluctuations practice self-monitoring of blood glucose (SMBG). For example, diabetic subjects may make insulin dosage adjustments before injection based upon the level of glucose in the blood. Adjustments are necessary since blood glucose levels vary day to day for a variety of reasons, e.g., exercise, stress, rates of food absorption, types of food, hormonal changes (pregnancy, puberty, etc.) and the like.
Present devices available for SMBG are complicated and difficult for many diabetics to use and often require them to obtain an adequate blood sample. Thus, despite the importance of SMBG, several studies have found that the proportion of individuals who self-monitor at least once a day significantly declines with age. This decrease is likely due simply to the fact that SMBG typically involves obtaining blood from a finger stick. Most diabetics, even those aware of the complications of hypo- and hyperglycemia, do not test frequently enough (for Type I [insulin dependent] diabetics this may be 6-8 times/D and for Type II diabetics controlled with oral agent testing should ideally be performed at least 2 times/D) because they consider obtaining blood to be significantly more painful than the self-administration of insulin and SMBG is far more time consuming and complicated. The FDA is fully aware of the many shortcomings of the devices used for SMBG, but newer technologies or matrices have not proven any more reliable.
There is a desire for a less invasive method of glucose measurement. Methods exist or are being developed for a minimally invasive glucose monitoring, which use body fluids other than blood (e.g., sweat, tears, or saliva) or subcutaneous fluid. Sweat and saliva are relatively easy to obtain, but their glucose concentration appears to lag in time significantly behind that of blood glucose. Unfortunately, tears, saliva and sweat have failed as viable matrices for use as surrogates for blood in monitoring glucose levels.
Billions of dollars have been spent on sensors that can be temporarily inserted into the subcutaneous tissues (usually of the abdomen) in order to measure glucose continuously. The fluid present between cells in this space is referred to as “interstitial fluid.” Continuous measurement of interstitial fluid could lead to the development of closed loop glucose control with insulin pumps. The ultimate goal is a device that could be implanted and would continuously measure glucose and provide insulin to tightly regulate glucose concentration. This goal has remained elusive and present sensors function for only a few days and interstitial fluid has been shown to be an average of the glucose concentration over periods of time that exceed those acceptable to sense rapid changes in glucose concentration, especially when hypoglycemia occurs.
Breath is a unique bodily fluid. Unlike blood, urine, feces, saliva, sweat and other bodily fluids, it is available on a breath to breath, and therefore continuous, basis. It is readily available for sampling non-invasively and because the lung receives all of the blood flow from the right side of the heart, measurements of analytes/compounds in breath correlate strongly and reproducibly with blood concentration. It is less likely to be associated with the transfer of serious infections than other bodily fluids and collection of samples is straightforward and painless. More importantly, certain compounds that are produced by the cellular lining of the airways, notably nitric oxide (NO), may be in higher concentration in the airways and therefore easily assessed in breath as opposed to blood, urine, and the like.
Exhaled breath, especially when exhaled through the mouth (in contrast to breath exhaled from the nose, which acts as a heat-moisture exchanger) is a complex fluid that contains 100% humidity at 37° C. (body temperature) and aerosol droplets that are derived from airway lining fluid, predominantly from fluid lining the alveoli but may also include contributions from non-alveolar areas. If the temperature of the collected sample is maintained at 37° C. or higher it will remain in this state and can be treated as a gas for compounds that are insoluble in water or readily diffuse out of water.
Truly simple, non-invasive methods of measuring glucose are not commercially available. Insofar as is known, glucose has not been previously reported as being detectable in exhaled breath condensates (EBC), let alone having any correlation with blood and condensate concentration. Thus, there is a need for a commercially available, non-invasive EBC sensing device that enables frequent monitoring of glucose levels in subjects.